Immunosuppressive effects of radiation on human dendritic cells: reduced IL-12 production on activation and impairment of naïve T-cell priming

Dendritic cells (DC) are professional antigen-presenting cells (APC) of the immune system, uniquely able to prime naïve T-cell responses. They are the focus of a range of novel strategies for the immunotherapy of cancer, a proportion of which include treating DC with ionising radiation to high dose. The effects of radiation on DC have not, however, been fully characterised. We therefore cultured human myeloid DC from CD14+ precursors, and studied the effects of ionising radiation on their phenotype and function. Dendritic cells were remarkably resistant against radiation-induced apoptosis, showed limited changes in surface phenotype, and mostly maintained their endocytic, phagocytic and migratory capacity. However, irradiated DC were less effective in a mixed lymphocyte reaction, and on maturation produced significantly less IL-12 than unirradiated controls, while IL-10 secretion was maintained. Furthermore, peptide-pulsed irradiated mature DC were less effective at naïve T-cell priming, stimulating fewer effector cells with lower cytotoxicity against antigen-specific targets. Hence irradiation of DC in vitro, and potentially in vivo, has a significant impact on their function, and may shift the balance between T-cell activation and tolerisation in DC-mediated immune responses

Rationale, design and methods for a community-based study of clustering and cumulative effects on chronic disease process and their effects on ageing: the Busselton healthy ageing study

Background: The global trend of increased life expectancy and increased prevalence of chronic and degenerative diseases will impact on health systems. To identify effective intervention and prevention strategies, greater understanding of the risk factors for and cumulative effects of chronic disease processes and their effects on function and quality of life is needed. The Busselton Healthy Ageing Study aims to enhance understanding of ageing by relating the clustering and interactions of common chronic conditions in adults to function. Longitudinal (3–5 yearly) follow-up is planned. Methods/design: Phase I (recruitment) is a cross-sectional community-based prospective cohort study involving up to 4,000 ‘Baby Boomers’ (born from 1946 to 1964) living in the Busselton Shire, Western Australia. The study protocol involves a detailed, self-administered health and risk factor questionnaire and a range of physical assessments including body composition and bone density measurements, cardiovascular profiling (blood pressure, ECG and brachial pulse wave velocity), retinal photography, tonometry, auto-refraction, spirometry and bronchodilator responsiveness, skin allergy prick tests, sleep apnoea screening, tympanometry and audiometry, grip strength, mobility, balance and leg extensor strength. Cognitive function and reserve, semantic memory, and pre-morbid intelligence are assessed. Participants provide a fasting blood sample for assessment of lipids, blood glucose, C-reactive protein and renal and liver function, and RNA, DNA and serum are stored. Clinically relevant results are provided to all participants. The prevalence of risk factors, symptoms and diagnosed illness will be calculated and the burden of illness will be estimated based on the observed relationships and clustering of symptoms and illness within individuals. Risk factors for combinations of illness will be compared with those for single illnesses and the relation of combinations of illness and symptoms to cognitive and physical function will be estimated. Discussion: This study will enable a thorough characterization of multiple disease processes and their risk factors within a community-based sample of individuals to determine their singular, interactive and cumulative effects on ageing. The project will provide novel cross-sectional data and establish a cohort that will be used for longitudinal analyses of the genetic, lifestyle and environmental factors that determine whether an individual ages well or with impairment

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

How a Stressed Local Public System Copes With People in Psychiatric Crisis

In order to bolster the public mental health safety net, we must first understand how these systems function on a day-to-day basis. This study explored how individual attributes and organizational interdependencies within one predominantly urban US county affected responses to individuals’ needs during psychiatric crises. We interviewed clinicians and managers within the crisis response network about people at immediate risk of psychiatric hospitalization, what had happened to them during their crises, and factors affecting services provided (N = 94 individuals and 9 agencies). Social network diagrams depicted patterns of referrals between agencies. Iterative coding of interview transcripts was used to contextualize the social network findings. Often, agencies saw crises through to resolution. However, providers also limited the types of people they served, leaving many people in crisis in limbo. This study illustrates how attributes of individuals with mental illness, service providers and their interactions, and state and federal policies intersect to shape the trajectories of individuals during psychiatric crises. Understanding both the structures of current local systems and their contexts may support continued evolution toward a more humane and robust safety net for some of our society’s most vulnerable members